We have demonstrated that lymphoid organs function as a major reservoir for human human immunodeficiency virus type 1 (HIV-1). We have demonstrated that during clinical latency, HIV accumulates in the lymphoid organs and replicates actively despite a low viral burden in peripheral blood. The histopathologic abnormalities are responsible for trapping of viral particles and sequestration of HIV-1 infected cells. Viral particles are trapped within the follicular dendritic cell (FDC) network of the germinal center. A progressive disruption of lymphoid tissue architecture is associated with disease progression. Efficient trapping of virus corresponds directly with the integrity of the FDC network. Viral burden and viral replication tend to equilibrate in late stage disease. A state of true microbiological latency does not exist during the course of HIV-1 infection. Peripheral blood does not accurately reflect the actual state of HIV disease. HIV disease is active and progressive during clinical latency. We have investigated virus expression and distribution in the gut associated lymphoid tissue. We have demonstrated trapping of virus in the FDC network associated with the lymphoglandular complexes disseminated in the gut. Rarely, isolated cells expressing HIV-1 RNA have bene observed in the gut. Similar levels of viral burden and replication have been observed in the gut. Similar levels of viral burden and replication have been found in mononuclear cells isolated from peripheral blood and bronchoalveolar lavage (BAL). We have investigated cytokine expression in peripheral blood and lymphoid tissues from the same patients and have demonstrated a decline in the levels of expression of interferon-gamma and interleukin-2 (IL-2) in both peripheral blood and lymphoid tissue associated with disease progression. Levels of expression of TNF-alpha and IL-10 did not change in the different stages of disease. Levels of expression of IL-6 increased in peripheral blood with disease progression. IL-4 was never expressed in both peripheral blood and lymphoid tissue in any stage of disease. Immunopathogenic insights gained from these studies will have important implications in the design of therapeutic strategies.